Pharmacogenetics of Alcohol: Treatment Implications
This study has been completed.
Sponsor:
University of Connecticut Health Center
Collaborators:
Information provided by (Responsible Party):
Jonathan Covault, University of Connecticut Health Center
ClinicalTrials.gov Identifier:
NCT00734656
First received: July 31, 2008
Last updated: March 26, 2012
Last verified: March 2012
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Purpose
This study will explore the hypothesis that effects of alcohol are in part mediated by increased production of neuroactive steroids, which interact with GABAA-receptors. We propose to study non-dependent drinkers using a 4-session within-subjects design in which alcohol / placebo is paired with dutasteride / placebo pretreatment. Dutasteride is a 5-alpha steroid reductase (5AR) inhibitor that limits the production of dihydrotestosterone and the 5a-reduced neuroactive steroids allopregnanolone, pregnanolone and 3a,5a-androstanediol.
| Condition | Intervention |
|---|---|
|
Alcohol Related Disorders Alcoholism Alcohol Abuse |
Drug: dutasteride + ethanol Drug: placebo medication + ethanol Drug: dutasteride + placebo alcohol Drug: placebo medication + placebo alcohol |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Factorial Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) |
| Official Title: | Subjective and Physiological Effects of Alcohol: Role of Genetic Variation and Adrenal Hormones |
Resource links provided by NLM:
MedlinePlus related topics:
Alcoholism
Drug Information available for:
Dutasteride
U.S. FDA Resources
Further study details as provided by University of Connecticut Health Center:
Primary Outcome Measures:
- Breath Alcohol [ Time Frame: 40 minutes after beginning drink ] [ Designated as safety issue: No ]Breath Alcohol level
- BAES Sedation Response, Average of 6 Time Points [ Time Frame: 40, 80, 120, 160, 210 and 240 minutes after start of drinking ] [ Designated as safety issue: No ]Biphasic Alcohol Effects Scale (BAES) Sedation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 sedation related questions regarding effects of alcohol. Total BAES sedation subscale score 0-70 with higher numbers indicating greater sedative effects of alcohol. [Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.]
- BAES Stimulation Response, Average of 6 Time Points [ Time Frame: 40, 80, 120, 160, 210 and 240 minutes after start of drinking ] [ Designated as safety issue: No ]Biphasic Alcohol Effects Scale (BAES)Simulation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 stimulation related questions regarding effects of alcohol. Total BAES stimulation subscale score 0-70 with higher numbers indicating greater stimulating effects of alcohol. [Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.]
Secondary Outcome Measures:
- Change in Serum 3a-androstanediol Glucuronide [ Time Frame: Baseline (pre medication administration) and 2-4 days post-medication (alcohol session) ] [ Designated as safety issue: No ]Ratio of serum 3a-androstanediol drawn prior to alcohol administration (2-4 days after medication administration) compared to the baseline level prior to medication dose. The pharmacologic effect of dutasteride was measured by assay of serum 5a-androstan-3a,17b-diol,17-glucuronide (aka 3a-androstanediol glucuronide) as a biochemical measure of 5a-reductase enzyme inhibition. 3a-androstanediol glucuronide is the primary metabolic excretion product of 3a,5a-androstane neuroactive steroids. The
| Enrollment: | 94 |
| Study Start Date: | March 2007 |
| Study Completion Date: | July 2011 |
| Primary Completion Date: | October 2010 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Placebo Comparator: Placebo medication + placebo alcohol |
Drug: placebo medication + placebo alcohol
placebo medication administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes
|
| Experimental: Placebo Medication + 0.8 gr/kg Ethanol |
Drug: placebo medication + ethanol
placebo medication administered 2-4 days prior to ingestion of 0.8 gr/kg ethanol divided between three drinks consumed over 36 minutes
|
| Experimental: 4 mg Dutasteride + Placebo Alcohol |
Drug: dutasteride + placebo alcohol
4 mg dutasteride administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes
Other Name: Avodart
|
| Experimental: 4 mg Dutasteride + 0.8 gr/kg Ethanol |
Drug: dutasteride + ethanol
4 mg dutasteride administered 2-4 days prior to ingestion of 0.8 mg/kg ethanol divided between three drinks consumed over 36 minutes
Other Name: Avodart
|
Detailed Description:
Alcohol has multiple pharmacological effects, though which of these effects relate to the risk of alcohol dependence is not clear. Animal studies indicate that the neuroactive steroid allopregnanolone is an alcohol-modulated endogenous agonist at GABAA receptors and that genetic variation in steroid 5a-reductase type I gene which generates neuroactive steroids, may moderate alcohol effects. To better define the role of neuroactive steroids we will conduct a laboratory study of non-alcohol dependent drinkers using a 4-session design in which alcohol/placebo beverage is paired with dutasteride/placebo pretreatment. Dutasteride, an inhibitor of both type I and type II 5a-reductase enzymes, blocks the production of 5a-reduced neuroactive steroids. This study will extend our preliminary findings with finasteride by including a) a placebo control for alcohol, b) a more specific inhibitor of both 5a-reductase isoenzymes, c) a larger group of subjects (including both light and heavy drinkers).
Eligibility| Ages Eligible for Study: | 21 Years to 45 Years |
| Genders Eligible for Study: | Male |
| Accepts Healthy Volunteers: | Yes |
Criteria
Inclusion Criteria:
- Main Study: Subjects will be healthy volunteers with or without parental history of alcoholism who are 21-45 years old and who have a BMI >18.5 and <32.5. Drinking history: All subjects must report at least one occasion in the prior month of drinking at least 3 drinks on a single day; additionally, LD subjects will be selected if they drink 1-3 drinks, 1-3 times per week (up to 5 drinks per week on average), with no more than one occasion in the past 2 months on which they drank >4 drinks. HD subjects will be selected if they report drinking at least 10 drinks per week, with at least one episode per week of heavy drinking.
Exclusion Criteria:
- Main Study: Subjects cannot have a current or past DSM-IV diagnosis of alcohol or drug dependence, current or past 24-months diagnosis of alcohol or drug abuse or another major psychiatric disorder, neurological illness, have had a hypersensitivity reaction to dutasteride, evidence of liver dysfunction, currently be using benzodiazepines, other psychotropic medications or medications that are known to influence steroid hormone levels or metabolism or modify the effects of alcohol. Nicotine-dependent subjects will be excluded to avoid the confounding effects of nicotine withdrawal during day-long laboratory sessions. Women are not allowed to participate. Subjects anticipating moving from the area during the period of their planned study participation will be excluded from study entry.
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00734656
Locations
| United States, Connecticut | |
| University of Connecticut Health Center | |
| Farmington, Connecticut, United States, 06030 | |
Sponsors and Collaborators
University of Connecticut Health Center
Investigators
| Principal Investigator: | Jonathan Covault, MD, PhD | University of Connecticut Health Center |
More Information
No publications provided
| Responsible Party: | Jonathan Covault, Associate Professor, University of Connecticut Health Center |
| ClinicalTrials.gov Identifier: | NCT00734656 History of Changes |
| Other Study ID Numbers: | 06-218S-2, 619, 5R01AA015606-02 |
| Study First Received: | July 31, 2008 |
| Results First Received: | October 27, 2011 |
| Last Updated: | March 26, 2012 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by University of Connecticut Health Center:
|
steroid 5Alpha Reductase dutasteride neuroactive steroid |
Additional relevant MeSH terms:
|
Alcoholism Alcohol-Related Disorders Substance-Related Disorders Mental Disorders Ethanol Dutasteride Anti-Infective Agents, Local Anti-Infective Agents |
Therapeutic Uses Pharmacologic Actions Central Nervous System Depressants Physiological Effects of Drugs Central Nervous System Agents 5-alpha Reductase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
ClinicalTrials.gov processed this record on May 16, 2013